Cartilage is a unique tissue that functions to cushion the impact between bones and is sensitive to age-associated changes that ultimately leads to osteoarthritis, a disease afflicting millions of elderly individuals. Collagen II is an abundant component of the cartilage matrix and its expression by the chondrocyte is altered during the progression of osteoarthritis. We are studying the molecular mechanisms that regulate chondrocyte gene expression with an emphasis on the control of type II collagen synthesis. The collagen II gene contains a DNA sequence that functions as a chondrocyte-specific enhancer of transcription and cell specific expression. Using DNA-affinity chromatography, we have partially purified a group of 3-4 proteins that bind to a specific DNA sequence in the enhancer and we are currently attempting to microsequence these proteins. Also, we have obtained a cDNA that encodes a protein that binds to the recognition sequence and we are currently characterizing this clone further. We are also characterizing in vitro and in vivo models to study the regulation of chondrocyte matrix synthesis and proliferation by growth factors and the activation of chondrogenesis by drugs. Finally, we have initiated studies to determine the pattern of gene expression in articular cartilage from different aged rats. These studies should eventually allow us to design novel therapies for osteoarthritis by stimulating chondrocyte proliferation and matrix synthesis.